Solid oral pharmaceutical composition

Abstract

The present invention relates to a solid oral pharmaceutical composition comprising ketorolac or one of the salts or derivatives thereof as active ingredient. The composition takes the form of a multi-layer pharmaceutical composition comprising at least one component comprising part of the total amount of ketorolac or one of the salts or derivatives thereof exhibiting prolonged release of the active ingredient and at least one second component comprising the remainder of the total amount of ketorolac or one of the salts or derivatives thereof exhibiting immediate release of the active ingredient. By providing a specific combination of immediate-release and prolonged-release components, it is possible to obtain a composition that provides coordinated release of the drug and improves the analgesic response through the use of ketorolac. The invention also includes the process of preparing such compositions and use thereof in preparing a medicament for pain treatment.

Description

ORAL SOLID PHARMACEUTICAL COMPOSITION FIELD OF INVENTION

[0001] The present invention relates to a solid oral pharmaceutical composition comprising ketorolac or one of its salts or derivatives as the active ingredient. The composition is in the form of a multilayer pharmaceutical composition comprising at least one component comprising part of the total amount of ketorolac or one of its salts or derivatives that exhibits prolonged release of the active ingredient and at least a second component comprising the remainder of the total amount of ketorolac or one of its salts or derivatives that exhibits immediate release of the active ingredient. By providing a specific combination of immediate- and prolonged-release components, it is possible to obtain a composition that provides coordinated drug release and improves the analgesic response of ketorolac. The invention also includes the process for preparing such compositions and their use in the preparation of a medicament for the treatment of pain. BACKGROUND OF THE INVENTION

[0002] Ketorolac is a drug first synthesized by Syntex, United States of America. The substance was described in US Patent 4,089,969, whose chemical structure is represented by Formula 1, and whose chemical name is (+)-5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylic acid. The best-known commercially available form of the compound is the tromethamine salt, represented by Formula 2. Formula 1 Formula 2

[0003] As a non-steroidal anti-inflammatory drug (NSAID), which inhibits prostaglandin synthesis, ketorolac is notably known for its anti-inflammatory, analgesic and antipyretic action, having proven effective in relieving moderate to severe pain, such as postpartum pain.

[0004] Ketorolac tromethamine is available in several administration forms, including oral tablets, intramuscular injection, intravenous injection, and ophthalmic solution. The route of administration depends on the severity of the pain and the desired speed of action. The oral dose of ketorolac is 20 mg as the first dose, followed by 10 mg every 4–6 hours.

[0005] In terms of efficacy, ketorolac tromethamine was 36 times more potent than phenylbutazone, approximately twice as potent as indomethacin, and three times more potent than naproxen in systemic anti-inflammatory activity, and its analgesic activity was stronger than that of aspirin. Clinical studies also indicated that the efficacy of a single dose of ketorolac was greater than that of morphine, pethidine, and pentazocine in moderate to severe postoperative pain (Buckley, M.M.-T., & Brogden, R.N. (1990). Ketorolac, A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs, 39(1), 86-109.).

[0006] Despite its potent analgesic, anti-inflammatory and antipyretic action, ketorolac has a short plasma half-life, ranging from 1.1 to 6.0 hours after oral administration of a single dose (Mroszczak, EJ Et al (1987). Ketorolac tromethamine absorption, distribution, metabolism, excretion and pharmacokinetics in animals and humans. Drug Metab. Dispos., 15(5), 618-626.), which implies frequent dosing of the drug to maintain the therapeutic effect and results in limited clinical utility.

[0007] An alternative to prolonging the therapeutic effect of a short half-life medication is the use of extended-release formulations. These types of formulations offer advantages, including reduced dosing frequency, maintenance of therapeutic levels, improved safety profile, increased therapeutic efficacy, and greater ease of administration. These formulations contribute to more effective, convenient, and safe treatment, improving patients' quality of life.

[0008] Formulations that promote the sustained release of ketorolac tromethamine are described in the prior art. For example, patent document KR20020024714 describes a sustained-release pellet consisting of a crystalline core with a size of 300-1000 micrometers, an inner layer containing ketorolac tromethamine, and an outer sustained-release layer containing Eudragit as the essential ingredient and, optionally, a water-soluble polymer.

[0009] Although effective in prolonging the therapeutic effect of short-half-life drugs, in some cases, extended-release formulations may have a slower onset of action compared to immediate-release formulations. This is an important consideration when prescribing or using extended-release medications, especially in situations where a rapid therapeutic response is required, such as acute pain conditions.

[0010] Thus, there is still a need for pharmaceutical compositions of ketorolac that exhibit a rapid onset of therapeutic action and, at the same time, exhibit prolonged release of the active ingredient, aiming at the coordinated release of the drug, the improvement of the analgesic response, as well as the reduction of the dosage frequency to be administered by the patient. SUMMARY OF THE INVENTION

[0011] A first object of the present invention relates to the oral solid pharmaceutical composition comprising about 10 mg to about 40 mg of ketorolac or one of its salts or derivatives per dosage unit, wherein said dosage unit comprises: (a) at least one first component exhibiting immediate release of active ingredient comprising about 10% to about 90% of the total mass amount of ketorolac, or one of its salts or derivatives, and pharmaceutically acceptable excipients; (b) at least one second component exhibiting prolonged release of active ingredient comprising about 10% to about 90% of the total mass amount of ketorolac, or one of its salts or derivatives, and pharmaceutically acceptable excipients; and (c) optionally, a coating layer surrounding components (a) and (b);

[0012] In a preferred embodiment, component b) of the composition of the present invention comprises a release matrix comprising at least one hydroxypropylmethylcellulose (HPMC) that has at least one of the following characteristics: a. degree of methoxyl substitution greater than about 1.4; b. percentage of methoxyl greater than about 22%; c. molar substitution of hydroxypropyl greater than about 0.21 moles of hydroxypropyl per mole of anhydroglucose; or d. percentage of hydroxypropyl greater than about 8.1%.

[0013] In a preferred embodiment, the pharmaceutical composition of the present invention comprises a dosage unit in the form of a bilayer tablet comprising approximately 20 mg per dosage unit of ketorolac tromethamine as the active ingredient, and pharmaceutically acceptable excipients, wherein said dosage unit comprises: (a) a first layer exhibiting immediate release of active ingredient comprising about 9.6 mg of ketorolac tromethamine; a mixture of lactose monohydrate and microcrystalline cellulose as diluent; croscarmellose sodium as disintegrant; anhydrous colloidal silicon dioxide as glidant and magnesium stearate as lubricant; (b) a second layer exhibiting prolonged release of active ingredient comprising about 10.4 mg of ketorolac tromethamine; about 50.0 mg of a release matrix based on hydroxypropyl methyl cellulose (HPMC); microcrystalline cellulose as diluent; anhydrous colloidal silicon dioxide as glidant and magnesium stearate as lubricant; and (c) optionally, a coating layer surrounding components (a) and (b); wherein said HPMC-based release matrix exhibits at least one of the following characteristics: (i) a degree of methoxyl substitution greater than about 1.4 and / or a methoxyl percentage greater than about 22%; and (ii) a molar substitution of hydroxypropyl greater than about 0.21 moles of hydroxypropyl per mole of anhydroglucose and / or a percentage of hydroxypropyl greater than about 8.1%.

[0014] A second object of the present invention relates to the process of preparing the composition as defined in this specification comprising the steps of: a. mixing between about 10% to about 90% of the total amount of ketorolac, or one of its salts or derivatives, with pharmaceutically acceptable excipients, followed by compression to form a first component (a); b. mixing between about 10% to about 90% of the total amount of ketorolac, or one of its salts or derivatives, with a release matrix based on hydroxypropyl cellulose (HPMC) and pharmaceutically acceptable excipients, followed by compression to form a second component (b); c. compressing components (a) and (b) to form a dosage unit; and; d. optionally, coating the dosage unit obtained in (c)

[0015] Finally, the present invention also deals with the use of the composition as defined in this specification in the preparation of a medicament for the treatment of pain. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention relates to a solid oral pharmaceutical composition comprising ketorolac or one of its salts or derivatives as an active ingredient, to the process for obtaining said composition, as well as to the use of said composition.

[0017] Ketorolac is a medication used to relieve moderate to severe pain. It belongs to the nonsteroidal anti-inflammatory drug (NSAID) class and is commonly administered orally, intramuscularly, or intravenously. Recommended doses of ketorolac tromethamine for analgesia may vary depending on the method of administration, the severity of the pain, and the individual patient's response. Generally, for the oral treatment of acute or chronic pain, the initial dose is usually 10 mg, followed by 10 mg every 4 to 6 hours if necessary, not exceeding 40 mg per day.

[0018] In a preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises about 10 mg to about 40 mg per dosage unit of ketorolac or one of its salts or derivatives as the active ingredient. Preferably, the solid oral pharmaceutical composition of the present invention comprises about 20 mg of ketorolac or one of its salts or derivatives as the active ingredient.

[0019] In a preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises about 10 mg to about 40 mg per dosage unit of ketorolac tromethamine as the active ingredient. Preferably, the solid oral pharmaceutical composition of the present invention comprises about 20 mg of ketorolac tromethamine as the active ingredient.

[0020] For the purposes of the present invention, a solid oral pharmaceutical composition comprises a drug form that is administered orally and is presented in a solid form, such as tablets, capsules, dragees, or tablets. It is one of the most common forms of drug presentation and is widely used due to its convenience, ease of administration, and stability.

[0021] The composition of the present invention is in the form of a multilayer pharmaceutical composition comprising at least one component comprising part of the total amount of ketorolac or one of its salts or derivatives that exhibits prolonged release of active ingredient and at least a second component comprising the remainder of the total amount of ketorolac or one of its salts or derivatives that exhibits immediate release of active ingredient.

[0022] For the purposes of the present invention, a multilayer pharmaceutical composition, also known as a multilayer tablet or sequential-release tablet, is a special form of solid oral pharmaceutical composition. In this type of formulation, different layers or zones are created within the tablet, each containing a specific combination of active drugs and excipients. Each layer of the multilayer pharmaceutical composition can have a different purpose. For example, one layer may contain an immediate-release drug to provide a rapid effect, while another layer may contain a modified-release or controlled-release drug to ensure gradual and sustained release over time. The advantage of these formulations is the possibility of administering multiple drugs at different release rates in a single tablet. single tablet. This can be especially useful when dealing with drug combinations that require different release profiles or when you want to avoid the need for multiple doses.

[0023] The term "component," for the purposes of the present invention, is used to designate a portion of the dosage form that comprises part of the total amount of active ingredient, optionally together with pharmaceutical excipients. Preferably, the compartments comprise a homogeneous mixture of components. Each compartment contains at least one type of active ingredient.

[0024] In a preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises at least a first component as an immediate release layer of active ingredient and at least a second component as a prolonged release layer of active ingredient.

[0025] The term "immediate release" as used within the context of the present invention refers to the fact that, within 120 minutes, preferably within 90 minutes, more preferably within 60 minutes and most preferably within 30 minutes, at least 80%, preferably at least 85%, more preferably at least 90% of the drug present in the immediate release compartment of active ingredient is dissolved or released. The term also refers to the fact that, within 120 minutes, preferably within 90 minutes, more preferably within 60 minutes and most preferably within 30 minutes, at least 25%, preferably at least 30% of the total amount of drug present in the dosage unit is dissolved or released.

[0026] The term "sustained release" as used within the context of the present invention refers to the fact that at least 95% of the drug present in the component is dissolved or released not earlier than 360 minutes, preferably not earlier than 420 minutes, and more preferably not earlier than 480 minutes. The term also refers to the fact that in 360 minutes, preferably in 420 minutes, and more preferably, within 480 minutes at least 80% of the total amount of drug present in the dosage unit is dissolved or released.

[0027] The release rate of an active ingredient from a solid oral pharmaceutical composition can be determined using various techniques within the skill of the art, with in vitro dissolution being the most commonly selected. In the in vitro dissolution method, the pharmaceutical composition is placed in a container with a dissolution medium that simulates the conditions of the gastrointestinal tract. The release of the active ingredient is monitored over time, and the release rate is determined by measuring the amount of active ingredient released at regular intervals. This assessment is performed using dissolution devices such as basket, paddle, or continuous-flow dissolution devices. A suitable test for determining dissolution is the Apparatus 2 test, according to U.S. Pharmacopeia 32-NF 27, described in General Chapter 711 (Dissolution).

[0028] Surprisingly, by providing a specific combination of immediate and prolonged release components, the inventors discovered that it is possible to obtain a coordinated and prolonged ketorolac release profile using the composition of the present invention, so that the analgesic response through the use of ketorolac is improved in relation to other oral solid pharmaceutical compositions containing ketorolate described in the state of the art.

[0029] Thus, a first aspect of the present invention relates to an oral solid pharmaceutical composition comprising between about 10 mg and about 40 mg per dosage unit of ketorolac or one of its salts or derivatives as active ingredient, wherein said dosage unit comprises: (a) at least one first component exhibiting immediate release of active ingredient comprising about 10% to about 90% of the total mass amount of ketorolac, or one of its salts or derivatives, and pharmaceutically acceptable excipients; and (b) at least one second component exhibiting prolonged release of active ingredient comprising about 10% to about 90% of the total mass amount of ketorolac, or one of its salts or derivatives; at least one release matrix; and pharmaceutically acceptable excipients.

[0030] In a preferred embodiment, the composition of the present invention comprises, per unit and dosage, about 10 mg to about 40 mg of ketorolac or one of its salts or derivatives, preferably between about 10 mg to about 30 mg of ketorolac, more preferably between about 15 mg to about 25 mg of ketorolac and even more preferably about 20 mg of ketorolac.

[0031] In a preferred embodiment, the first component (a) exhibiting immediate release of active and the second component (b) exhibiting sustained release of active of the dosage unit of the composition of the present invention individually comprise about 10% to about 90%, preferably about 30% to about 70%, preferably about 40% to about 60%, of the total mass amount per dosage unit of ketorolac. In a preferred embodiment, component (a) comprises about 48% of the total mass amount per dosage unit of ketorolac and component (b) comprises about 52% of the total mass amount per dosage unit of ketorolac.

[0032] In a preferred embodiment, the first component (a) exhibiting immediate release of active and the second component (b) exhibiting sustained release of active of the dosage unit of the composition of the present invention individually comprise about 1.0 mg to about 36.0 mg, preferably about 3.0 mg to about 28.0 mg, more preferably about 4.0 mg to about 24.0 mg, still more preferably about 8.0 mg to about 12.0 mg of the total amount by mass per dosage unit of ketorolac. In a preferred embodiment, component (a) comprises about 9.6 mg of ketorolac or one of its salts or derivatives and component (b) comprises about 10.4 mg ketorolac or one of its salts or derivatives.

[0033] In the context of the present invention, a release matrix can be defined as a system used to control the rate of release of the active ingredient over time. These matrices can be solid or semi-solid and are designed to maintain the drug in a stable form and allow its controlled release. There are different types of release matrices used in extended-release pharmaceutical compositions. Some common examples include hydrophilic matrices, lipophilic matrices, and mixed matrices. Hydrophilic matrices are composed of hydrophilic polymers that have the ability to absorb water and form a gel, creating a physical barrier that controls drug release, such as hydroxypropylmethyl cellulose (HPMC), methyl cellulose, sodium alginate, and carboxymethyl cellulose.Lipophilic release matrices are formulated with lipophilic polymers that slow drug release through diffusion through the matrix, such as polyesters, aliphatic polyesters, and poly(lactic-co-glycolic acid). Mixed release matrices combine hydrophilic and lipophilic polymers to achieve sustained and controlled drug release; the combination of polymers allows for greater flexibility in controlling the release rate.

[0034] In a preferred embodiment, component (b) exhibiting prolonged release of the active ingredient of the composition of the present invention comprises a hydrophilic release matrix. Preferably, said hydrophilic release matrix is ​​based on hydroxypropylmethyl cellulose (HPMC).

[0035] Hydroxypropylmethylcellulose (HPMC) is a hydrophilic polymer used as a drug delivery matrix in sustained-release solid pharmaceutical compositions. It is a cellulose derivative and has properties that make it suitable for this purpose. HPMC can be used as a hydrophilic release polymer in solid matrices to control drug release over time. When incorporated into a solid pharmaceutical composition, HPMC forms A matrix capable of absorbing water and forming a gel when in contact with biological fluids. This gel-forming ability allows HPMC to control drug release in two main ways. The first involves drug diffusion through the matrix, where HPMC forms a physical barrier that slows drug diffusion out of the matrix. Therefore, drug dissolved in water or biological fluids must pass through the HPMC gel to be released, resulting in a sustained and prolonged release over time. The second involves enzymatic degradation or hydrolysis of the matrix in the presence of water, resulting in the gradual release of the drug incorporated in the matrix.

[0036] The drug release rate can be controlled by the HPMC concentration and viscosity, particle size, drug-to-HPMC mass ratio, and the presence of other excipients in the formulation. The viscosity of hydroxypropylmethylcellulose (HPMC) is determined by several characteristics, including the degree of substitution, the ratio of hydroxypropylmethylation to methoxylation, the molecular weight, and the concentration of the HPMC solution. Modifying these parameters allows for the adjustment of the release rate and drug release kinetics.

[0037] Surprisingly, the inventors of the present invention found that by adjusting the parameters of the HPMC-based release matrix in terms of viscosity and ketorolac / HPMC ratio, as well as the ratio between the concentration of ketorolac in the immediate-release component and in the extended-release component, the composition of the present invention resulted, which presents a coordinated active release profile that is ultimately useful for improving the analgesic response by the use of ketorolac.

[0038] In the context of the present invention, the degree of methoxyl substitution (MS) of the hydroxypropylmethyl cellulose-based release matrix is ​​a measure of the average amount of methoxyl (CH3O-) groups substituted on the glucose units of the cellulose. The degree of methoxyl substitution (MS) is expressed as a fraction, the unit of measurement of which is dimensionless, since which represents a ratio of the number of substituted methoxyl groups to the number of anhydroglucose units, or as a percentage of substituted methoxyl groups relative to the total number of anhydroglucose units. An HPMC with a higher MS will have more methoxyl groups in its structure, which will result in different properties compared to an HPMC with a lower MS.

[0039] In the context of the present invention, molar hydroxypropyl substitution (MHS) is a measure of the average number of hydroxypropyl groups (-CH2CHOHCH3) substituted on the glucose units of cellulose. Like the degree of methoxyl substitution (MS) discussed previously, molar hydroxypropyl substitution is also expressed as a ratio of the number of moles of substituted hydroxypropyl groups to the number of moles of anhydroglucose, or as a percentage of hydroxypropyl moles as a function of the total number of moles of glucose in the cellulose.

[0040] In a preferred embodiment, the HPMC-based release matrix comprised in component (b) of the composition of the present invention has a degree of methoxyl substitution of greater than, or equal to, about 1.0 and less than, or equal to, about 2.2, preferably a degree of methoxyl substitution of greater than, or equal to, about 1.4 and less than, or equal to, about 2.2, even more preferably a degree of methoxyl substitution of greater than, or equal to, about 1.8 and less than, or equal to, about 2.0. In a preferred embodiment, the HPMC-based release matrix comprised in component (b) of the composition of the present invention has a degree of methoxyl substitution of about 1.9.

[0041] In a preferred embodiment, the HPMC-based release matrix comprised in component (b) of the composition of the present invention has a degree of methoxyl substitution expressed as a percentage of methoxyl that is greater than, or equal to, about 15.0% and less than, or equal to, about 30.0%, preferably greater than, or equal to, about 22.0% and less than, or equal to, about 30.0%, preferably greater than, or equal to, about 28.0% and less than, or equal to, about 30.0%. In a In a preferred embodiment, the HPMC-based release matrix comprised in component (b) of the composition of the present invention has a degree of methoxyl substitution expressed as a percentage of methoxyl equal to approximately 29.0%.

[0042] In a preferred embodiment, the HPMC-based release matrix comprised in component (b) of the composition of the present invention has a hydroxypropyl molar substitution of greater than, or equal to, about 0.0 and less than, or equal to, about 0.30, preferably greater than, or equal to, about 0.21 and less than, or equal to, about 0.30, even more preferably greater than, or equal to, about 0.21 and less than, or equal to, about 0.23. In a preferred embodiment, the HPMC-based release matrix comprised in component (b) of the composition of the present invention has a hydroxypropyl molar substitution degree of about 0.23.

[0043] In a preferred embodiment, the HPMC-based release matrix comprised in component (b) of the composition of the present invention has a molar substitution of hydroxypropyl expressed as a percentage of hydroxypropyl of greater than, or equal to, about 0.0 and less than, or equal to, about 10.0%, preferably greater than, or equal to, about 8.1% and less than, or equal to, about 9.0%, even more preferably greater than, or equal to, about 8.1% and less than, or equal to, about 8.5%. In a preferred embodiment, the HPMC-based release matrix comprised in component (b) of the composition of the present invention has a molar substitution of hydroxypropyl expressed as a percentage of hydroxypropyl of about 8.5%.

[0044] In a preferred embodiment, the composition of the present invention promotes the release or dissolution of at least 25%, preferably at least 45% of the total amount of drug present in the dosage unit in 30 minutes, when the dissolution test is performed according to US Pharmacopoeia 32-NF 27, General Chapter 711 (Dissolution) and Apparatus 2.

[0045] In a preferred embodiment, the composition of the present invention promotes the release or dissolution of at least 40%, preferably by least 50%, more preferably at least 75% of the total amount of drug present in the dosage unit in 90 minutes, when the dissolution test is performed in accordance with US Pharmacopoeia 32-NF 27, General Chapter 711 (Dissolution) and Apparatus 2.

[0046] In a preferred embodiment, the composition of the present invention promotes the release or dissolution of at least 80%, preferably at least 100%, of the total amount of drug present in the dosage unit in 480 minutes, when the dissolution test is performed according to US Pharmacopoeia 32-NF 27, General Chapter 711 (Dissolution) and Apparatus 2.

[0047] In a preferred embodiment, the ketorolac / HPMC mass ratio in component (b) of the composition of the present invention ranges from about 1.0:10.0 to about 1.0:2.0. Preferably, the ketorolac / HPMC mass ratio is about 1.0:5.0, more preferably about 1.0:4.8.

[0048] In the context of this invention, pharmaceutically acceptable excipients are substances used in drug formulations to perform various functions, such as aiding in drug stability, processability, administration, and acceptance. They do not possess direct pharmacological activity, but play a crucial role in drug development and production. Pharmaceutically acceptable excipients are selected based on strict criteria, taking into account their safety, compatibility with the active ingredients, stability, bioavailability, interaction with the human body, and regulatory requirements. Technicians and experts in this field have the necessary knowledge to evaluate, select, and formulate appropriate excipients to ensure drug efficacy and safety.Examples of pharmaceutically acceptable excipients and their properties can be found in Sheskey PJ, Hancock BC, Moss GP, and Goldfarb DJ (2020) Handbook of Pharmaceutical Excipients. 9th edition, Pharmaceutical Press. Within the context of this definition, pharmaceutically acceptable excipients can be classified according to their function in the composition to which they are added. These ingredients are introduced, playing the role of diluents, disintegrants, glidants, lubricants, pigments, preservatives, flavorings, among others.

[0049] In a preferred embodiment, the composition of the present invention comprises at least one pharmaceutically acceptable excipient in each of components (a) and (b) described above. Also in a preferred embodiment, components (a) and (b) of the composition of the present invention individually comprise at least one pharmaceutically acceptable excipient selected from the group consisting of diluents, disintegrants, glidants, lubricants, and combinations thereof.

[0050] Diluents, in the context of the present invention, are excipients used to increase the volume and adjust the dose of solid drugs, such as tablets and capsules, and are added to the formulation to facilitate uniformity of the mixture and ensure that the appropriate dose of the active ingredient is achieved. Some examples of diluents, in the context of the present invention, include anhydrous lactose, lactose monohydrate, microcrystalline cellulose, starch, dibasic calcium phosphate, mannitol, sorbitol, sucrose, and mixtures thereof.

[0051] In a preferred embodiment, components (a) and (b) of the composition of the present invention individually comprise at least one diluent. Preferably, the diluents of the composition of the present invention are selected from the group consisting of anhydrous lactose, lactose monohydrate, microcrystalline cellulose and mixtures thereof.

[0052] In a preferred embodiment, component (a) of the composition of the present invention comprises two diluents selected from the group consisting of anhydrous lactose, lactose monohydrate, microcrystalline cellulose and mixtures thereof. Preferably, component (a) comprises a mixture of diluents consisting of lactose monohydrate and microcrystalline cellulose.

[0053] In a preferred embodiment, component (b) of the composition of the present invention comprises a diluent selected from the group consisting of of anhydrous lactose, lactose monohydrate, microcrystalline cellulose and mixtures thereof. Preferably, component (b) comprises the diluent microcrystalline cellulose.

[0054] Disintegrants, in the context of the present invention, are pharmaceutical excipients added to drug formulations to promote the rapid disintegration of tablets or capsules when they come into contact with a liquid, such as water, in the gastrointestinal tract. Their main function is to ensure that the drug dissolves and becomes available for absorption by the body. Some examples of disintegrants, in the context of the present invention, include croscarmellose sodium, crospovidone, sodium starch glycolate, polyvinylpyrrolidone (PVP), sodium carboxymethyl cellulose, and mixtures thereof.

[0055] In a preferred embodiment, component (a) of the composition of the present invention comprises at least one disintegrant. Preferably, the disintegrants of the composition of the present invention are selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, polyvinylpyrrolidone (PVP), sodium carboxymethyl cellulose and mixtures thereof. Preferably, component (a) of the composition of the present invention comprises a disintegrant consisting of croscarmellose sodium.

[0056] Glidants, in the context of this invention, are pharmaceutical excipients used in drug formulations to improve flowability and reduce the adhesion of powders and granules during manufacturing processes such as mixing, compression, and coating. These excipients help prevent excessive friction between drug particles and machine surfaces, facilitating material flow and preventing agglomeration. Glidants act by reducing cohesion between drug particles, allowing for a smoother and more uniform flow. They are especially useful in tablet compression processes, where adhesion can result in problems such as weight variations, excessive equipment wear, and difficulty releasing tablets from dies. Glidants can be solid or liquid substances and are added in small amounts during the process. formulation process, being mixed homogeneously with the other ingredients to ensure uniform distribution. Some examples of glidants, in the context of the present invention, include silicon dioxide, titanium dioxide, colloidal silica, magnesium stearate, talc, and mixtures thereof.

[0057] In a preferred embodiment, components (a) and (b) of the composition of the present invention individually comprise at least one glidant. Preferably, the glidant of the composition of the present invention is selected from the group consisting of silicon dioxide, titanium dioxide, magnesium stearate, talc and mixtures thereof. Preferably, components (a) and (b) of the composition of the present invention individually comprise a glidant consisting of colloidal silicon dioxide.

[0058] Lubricants, in the context of this invention, are excipients used to reduce friction and adhesion between drug particles during the tablet compression process. They are added in small amounts to formulations to improve the flowability of powders and granules. Lubricants act by forming a lubricating layer on the particles, reducing the coefficient of friction and improving sliding between them. This helps prevent adhesion between the particles and the die surfaces of compression equipment, facilitating the release of tablets after compression. Furthermore, lubricants can also help reduce wear and friction between compression tools, extending their service life and ensuring the quality of the tablets produced.Some examples of lubricants, in the context of the present invention, include magnesium stearate, talc, silicon dioxide, sodium stearyl fumarate, stearic acid, polyethylene glycol (PEG) and mixtures thereof.

[0059] In a preferred embodiment, components (a) and (b) of the composition of the present invention individually comprise at least one lubricant. Preferably, the lubricant of the composition of the present invention is selected from the group consisting of magnesium stearate, talc, carbon dioxide silicon, sodium stearyl fumarate, stearic acid, polyethylene glycol (PEG) and mixtures thereof. Preferably, components (a) and (b) of the composition of the present invention individually comprise a lubricant consisting of magnesium stearate.

[0060] Optionally, in one embodiment of the present invention, components (a) and (b) of the composition of the present invention individually comprise at least one pigment.

[0061] Pigments, in the context of the present invention, are substances used to impart color to medications, primarily tablets, capsules, and other solid products. They are added in controlled amounts to provide visual identification, facilitate the differentiation of medications of different dosages or formulations, and improve patient acceptance and recognition. Some examples of pigments, in the context of the present invention, include iron oxides, such as red iron oxide, yellow iron oxide, and black iron oxide, titanium dioxide, indigo carmine, tartrazine, zinc oxide, and mixtures thereof.

[0062] In a preferred embodiment, at least one of the components (a) and (b) of the composition of the present invention comprises at least one pigment selected from the group consisting of red iron oxide, yellow iron oxide and black iron oxide, titanium dioxide, indigo carmine, tartrazine, zinc oxide and mixtures thereof.

[0063] Optionally, the solid oral pharmaceutical composition of the present invention comprises a coating layer (c) surrounding components (a) and (b)

[0064] In the context of the present invention, the term "coating" refers to a layer that at least partially covers one of the components (a) and (b) and is applied by various coating processes known in the art. Examples of coating include polyvinyl alcohol, hydroxypropylmethyl cellulose (HPMC), methyl cellulose, polyethylene glycol (PEG), acrylic polymers, sodium alginate, gelatin, and shellac, and mixtures thereof. Coatings, within the context of the present invention, may also additionally include pigments as defined above.

[0065] In a preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises a dosage unit in the pharmaceutical form of a bilayer tablet comprising components (a) and (b) as defined above.

[0066] In a preferred embodiment, the salt or derivative of ketorolac is ketorolac tromethamine.

[0067] Based on the above definitions, a first object of the present invention relates to a solid oral pharmaceutical composition comprising about 10 mg to about 40 mg of ketorolac or one of its salts or derivatives per dosage unit, wherein said dosage unit comprises: (a) at least one first component exhibiting immediate release of active ingredient comprising about 10% to about 90% of the total mass amount of ketorolac, or one of its salts or derivatives, and pharmaceutically acceptable excipients; (b) at least one second component exhibiting prolonged release of active ingredient comprising about 10% to about 90% of the total mass amount of ketorolac, or one of its salts or derivatives, and pharmaceutically acceptable excipients; and (c) optionally, a coating layer surrounding components (a) and (b);

[0068] In a preferred embodiment of the first object of the present invention, component b) of the composition of the present invention comprises a release matrix comprising at least one hydroxypropylmethyl cellulose (HPMC) that presents at least one of the following characteristics: a. degree of methoxyl substitution greater than about 1.4; b. percentage of methoxyl greater than about 22%; c. molar substitution of hydroxypropyl greater than about 0.21 moles of hydroxypropyl per mole of anhydroglucose; or d. percentage of hydroxypropyl greater than about 8.1%.

[0069] In an even more preferred embodiment of the first object of the present invention, the pharmaceutical composition of the present invention comprises a dosage unit in the form of a bilayer tablet comprising approximately 20 mg per dosage unit of ketorolac tromethamine as the active ingredient, and pharmaceutically acceptable excipients, in which said dosage unit comprises: (a) a first layer exhibiting immediate release of active ingredient comprising about 9.6 mg of ketorolac tromethamine; a mixture of lactose monohydrate and microcrystalline cellulose as diluent; croscarmellose sodium as disintegrant; anhydrous colloidal silicon dioxide as glidant and magnesium stearate as lubricant; (b) a second layer exhibiting prolonged release of active ingredient comprising about 10.4 mg of ketorolac tromethamine; about 50.0 mg of a release matrix based on hydroxypropyl methyl cellulose (HPMC); microcrystalline cellulose as diluent; anhydrous colloidal silicon dioxide as glidant and magnesium stearate as lubricant; and (c) optionally, a coating layer surrounding components (a) and (b); wherein said HPMC-based release matrix exhibits at least one of the following characteristics: (iii) a degree of methoxyl substitution greater than about 1.4 and / or a methoxyl percentage greater than about 22%; and (iv) a molar substitution of hydroxypropyl greater than about 0.21 moles of hydroxypropyl per mole of anhydroglucose and / or a percentage of hydroxypropyl greater than about 8.1%.

[0070] In an even more preferred embodiment of the first object of the present invention, component b) of the composition of the present invention comprises a release matrix comprising at least one hydroxypropylmethylcellulose (HPMC) that has the following characteristics: a. degree of methoxyl substitution of about 1.9; or b. percentage of methoxyl of about 29%; and c. molar substitution of hydroxypropyl of about 0.23 moles of hydroxypropyl per mole of anhydroglucose; or d. percentage of hydroxypropyl of about 8.5%.

[0071] A second aspect of the present invention relates to the process of preparing the multicomponent oral solid pharmaceutical composition comprising ketorolac as the active ingredient, as defined above.

[0072] In a preferred embodiment, the process of preparing the solid oral pharmaceutical composition is carried out using the direct dry compression technique.

[0073] In the context of the present invention, direct dry compression can be defined as a tablet manufacturing method that involves compacting the formulation ingredients in a single step, without the need for the addition of wet granulating agents or prior drying. It is an efficient and widely used process in the pharmaceutical industry to produce solid tablets. In this process, the active ingredients and excipients are homogeneously mixed, and the resulting mixture is fed into a tablet compression machine. The compression machine applies a force to compact the mixture into a die, resulting in the formation of tablets.

[0074] Direct compression of multilayer tablets is a manufacturing process in which at least two different formulations are compressed in distinct layers to form a single bilayer tablet. This method is commonly used to combine two incompatible active ingredients, achieving sequential release of drugs or provide different dosages in a single tablet.

[0075] In a preferred embodiment, the process of preparing the solid oral pharmaceutical composition, the composition of the present invention, results in the formation of a tablet comprising components (a) and (b) defined above. Preferably, the process described herein results in the formation of a bilayer tablet comprising components (a) and (b). Still preferably, the process described herein results in the formation of a bilayer tablet comprising components (a) and (b) coated by a coating layer (c).

[0076] Thus, a first object of the second aspect of the present invention relates to a process for preparing the oral solid pharmaceutical composition as defined above, such process comprising the steps of: a. mixing between about 10% to about 90% of the total amount of ketorolac, or one of its salts or derivatives, with pharmaceutically acceptable excipients, optionally followed by compression to form a first component (a); b. mixing between about 10% to about 90% of the total amount of ketorolac, or one of its salts or derivatives, with a release matrix based on hydroxypropyl cellulose (HPMC) and pharmaceutically acceptable excipients, optionally followed by compression to form a second component (b) in which steps (a) and (b), which can be performed in any order or concomitantly.

[0077] In a preferred embodiment, the process of preparing the composition of the present invention additionally comprises the step: c. compressing components (a) and (b) to form a dosage unit.

[0078] In a preferred embodiment, the process for preparing the composition of the present invention additionally comprises the step: d. coating the dosage unit obtained in (c).

[0079] Finally, a third aspect of the present invention relates to the use of the composition as defined in this specification in the preparation of a medicament for the treatment of pain.

[0080] The present invention is defined in greater detail in the following examples. It should be understood, however, that such examples indicate preferred embodiments according to the invention, but do not limit its scope, which is defined by the present specification and the claims appended hereto. EXAMPLE 1 - Composition of coated tablet The qualitative and quantitative composition of the tablet of the present example is described in Table 1 below. Table 1 Qty / dose (mg) Component a: Ketorolac tromethamine 9.600 Lactose monohydrate 161,400 Microcrystalline cellulose 14,800 Croscarmellose sodium 10,000 Silicon dioxide 2,000 Red iron oxide 0.200 Magnesium Stearate 2,000 Component b: Ketorolac tromethamine 10,400 Hydroxypropylmethylcellulose 50,000 Microcrystalline cellulose 135,600 Anhydrous colloidal silicon dioxide 2,000 Magnesium Stearate 2,000 Coating: Mixture of polyvinyl alcohol, carbon dioxide 11,800 titanium, polyethylene glycol and talc Red iron oxide 0.200

[0081] The formulation obtained is in the form of a coated bilayer tablet and has a component "a" corresponding to the first layer, which provides immediate release of the active ingredient, and a component "b" corresponding to the second layer, which provides prolonged release of the active ingredient. The total amount of ketorolac tromethamine in each dosage unit of the composition obtained in this example is 20.0 mg. Hydroxypropyl methylcellulose (HPMC) having a degree of methoxyl substitution of approximately 1.9, a methoxyl percentage of approximately 29, a hydroxypropyl molar substitution of approximately 0.23 moles of hydroxypropyl per mole of anhydroglucose, and a hydroxypropyl percentage of approximately 8.5% was used as the release matrix in the composition of compartment b. A batch of the composition described above was obtained by means of the direct compression technique.

[0082] To obtain the immediate-release layer, approximately 48% of the total amount of ketorolac tromatamol, lactose, microcrystalline cellulose, and croscarmellose sodium are passed through a 1.0 mm mesh and mixed until a homogeneous mixture is obtained. To this mixture are added silicon dioxide, magnesium stearate, and red iron oxide previously passed through a 60 mesh mesh. The mixture is then compressed with a 10.0 mm punch in a rotary tablet punching machine.

[0083] To obtain the extended-release layer, approximately 52% of the total amount of ketorolac tromatamol, hydroxypropylmethylcellulose, microcrystalline cellulose, anhydrous colloidal silicon dioxide, and magnesium stearate are passed through an 80-mesh screen and mixed until a homogeneous mixture is obtained. The mixture is then compressed with a 10.0 mm punch on a rotary tableting machine.

[0084] The bilayer tablet according to the composition of this example is then obtained. First, the immediate-release layer is placed in the die cavity and compressed, and second, the extended-release layer is placed and the two layers are compressed. Finally, the tablet is coated with a hydroalcoholic solution containing a mixture of polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and red iron oxide. EXAMPLE 2 - In vitro dissolution study

[0085] The rate of ketorolac tromethamine released from bilayer tablets manufactured according to Example 1 was determined using the United States Pharmacopeia (USP) XXIV dissolution test apparatus II (paddle method) with 8-mesh basket anchors, employing 900 mL Potassium Phosphate Buffer pH 6.8 as the dissolution medium and a rotation speed of 50 rpm.

[0086] The ketorolac content released into the dissolution medium was measured using high-performance liquid chromatography (HPLC) from aliquots sampled 30 minutes, 90 minutes, and 480 minutes after the tablets obtained in Example 1 were introduced into the dissolution medium. The study was conducted in sextuplicate.

[0087] Table 2 below shows the average dissolution rate obtained for tablets manufactured according to Example 1: Table 2 Time Average content Average content (tmiii) (minutes) minimum asset released (%) maximum asset released (%) so 25.0 45.0 so 50.0 75.0 Usage 80.0 -

[0088] From the analysis of the table above, it can be seen that there is an immediate release (up to 30 min) of approximately 45.0% of the total amount of active ingredient. These levels correspond to the ketorolac tromethamine content used in the immediate-release layer of the composition analyzed (approximately 48% of the total amount of active ingredient). From 90 minutes onward, on the other hand, it can be seen that the remaining amount of ketorolac tromethamine used in the composition analyzed (approximately 52%) is released gradually over the analyzed time.

[0089] Thus, it is possible to conclude that the composition of the present invention provides coordinated release of the drug, in order to improve the analgesic response through the use of ketorolac, that is, the dose of ketorolac provided in the first 30 minutes promotes the improvement of the acute analgesic response, and this analgesic effect is maintained through the prolonged release of the active ingredient provided by the composition of the present invention.

Claims

CLAIMS 1. Solid oral pharmaceutical composition CHARACTERIZED by the fact that it comprises approximately 10 mg to approximately 40 mg per dosage unit of ketorolac or one of its salts or derivatives as active ingredient and pharmaceutically acceptable excipients, in which said dosage unit comprises: (a) at least one first component exhibiting immediate release of active ingredient comprising about 10% to about 90% of the total mass amount of ketorolac, or one of its salts or derivatives, and pharmaceutically acceptable excipients; (b) at least one second component exhibiting prolonged release of active ingredient comprising about 10% to about 90% of the total mass amount of ketorolac, or one of its salts or derivatives; at least one release matrix based on hydroxypropylmethyl cellulose (HPMC); and pharmaceutically acceptable excipients; and (c) optionally, a coating layer surrounding components (a) and (b); wherein said HPMC-based release matrix exhibits at least one of the following characteristics: a. a degree of methoxyl substitution greater than about 1.4; or b. a methoxyl percentage greater than about 22%.

2. COMPOSITION, according to claim 1, CHARACTERIZED by the fact that said HPMC-based release matrix additionally presents the following characteristics: c. Molar substitution of hydroxypropyl greater than about 0.21 moles of hydroxypropyl per mole of anhydroglucose; or d. percentage of hydroxypropyl greater than about 8.1%.

3. COMPOSITION, according to claims 1 or 2, CHARACTERIZED by the fact that it promotes the release of about at least about 25%, preferably at least about 45%, more preferably at least about 50% and even more preferably at least 60% of the total amount of ketorolac in 30 minutes, when at pH 6.

8.

4. COMPOSITION, according to claims 1 or 2, CHARACTERIZED by the fact that it promotes the release of at least 80%, preferably at least 100% of the total amount of ketorolac in 480 minutes, when at pH 6.

8.

5. COMPOSITION, according to claims 1 to 4, CHARACTERIZED by the fact that the mass ratio between ketorolac and the HPMC-based release matrix in component (b) varies between about 1:10 and about 1:

2.

6. COMPOSITION, according to claim 5, CHARACTERIZED by the fact that the mass ratio between ketorolac and the HPMC-based release matrix in component (b) is about 1:

5.

7. COMPOSITION, according to any one of claims 1 to 6, CHARACTERIZED by the fact that components (a) and (b) of the dosage unit individually comprise about 30% to about 70%, preferably about 40% to about 60%, of the total mass amount per dosage unit of ketorolac.

8. COMPOSITION, according to claim 7, CHARACTERIZED by the fact that component (a) comprises about 48% of the total amount by mass per dosage unit of ketorolac and component (b) comprises about 52% of the total amount by mass per dosage unit of ketorolac.

9. COMPOSITION, according to any one of claims 1 to 8, CHARACTERIZED by the fact that components (a) and (b) individually comprise at least one pharmaceutically acceptable excipient selected from from the group consisting of diluents, disintegrants, glidants, lubricants, pigments, dyes and their combinations.

10. COMPOSITION, according to claim 9, CHARACTERIZED by the fact that the at least one diluent is selected from the group consisting of anhydrous lactose, lactose monohydrate, microcrystalline cellulose and mixtures thereof.

11. COMPOSITION, according to claim 9, CHARACTERIZED by the fact that the at least one disintegrant is selected from the group consisting of croscarmellose sodium and mixtures thereof.

12. COMPOSITION, according to claim 9, CHARACTERIZED by the fact that the at least one glidant is selected from the group consisting of anhydrous colloidal silicon dioxide and mixtures thereof.

13. COMPOSITION, according to claim 9, CHARACTERIZED by the fact that the at least one lubricant is selected from the group consisting of magnesium stearate and mixtures thereof.

14. COMPOSITION, according to any one of claims 1 to 13, CHARACTERIZED by the fact that the dosage unit is a bilayer tablet.

15. COMPOSITION, according to any one of claims 1 to 14, CHARACTERIZED by the fact that ketorolac or one of its salts or derivatives is ketorolac tromamol.

16. Pharmaceutical composition of bilayer tablet CHARACTERIZED by the fact that it comprises approximately 20 mg per dosage unit of ketorolac tromethamine as the active ingredient and pharmaceutically acceptable excipients, in which said dosage unit comprises: (a) a first layer exhibiting immediate release of active ingredient comprising about 9.6 mg of ketorolac tromethamine; a mixture of lactose monohydrate and microcrystalline cellulose as diluent; croscarmellose sodium as disintegrant; anhydrous colloidal silicon dioxide as a glidant and magnesium stearate as a lubricant; (b) a second layer exhibiting prolonged release of active ingredient comprising about 10.4 mg of ketorolac tromethamine; about 50.0 mg of a release matrix based on hydroxypropyl methyl cellulose (HPMC); microcrystalline cellulose as diluent; anhydrous colloidal silicon dioxide as glidant and magnesium stearate as lubricant; and (c) optionally, a coating layer surrounding components (a) and (b); wherein said HPMC-based release matrix exhibits at least one of the following characteristics: (i) a degree of methoxyl substitution greater than about 1.4 and / or a methoxyl percentage greater than about 22%; and (ii) a molar substitution of hydroxypropyl greater than about 0.21 moles of hydroxypropyl per mole of anhydroglucose and / or a percentage of hydroxypropyl greater than about 8.1%.

17. PROCESS for preparing a composition as defined in any one of claims 1 to 16, CHARACTERIZED by the fact that it comprises the steps of: a. mixing between about 10% to about 90% of the total amount of ketorolac, or one of its salts or derivatives, with pharmaceutically acceptable excipients, followed by compression to form a first component (a); b. mixing between about 10% to about 90% of the total amount of ketorolac, or one of its salts or derivatives, with a release matrix based on hydroxypropyl cellulose (HPMC) and pharmaceutically acceptable excipients, followed by compression to form a second component (b); c. compressing components (a) and (b) to form a dosage unit; and d. optionally, coat the dosage unit obtained in (c).

18. The process of claim 17, wherein said HPMC-based release matrix has at least one of the following characteristics: (i) a degree of methoxyl substitution greater than about 1.4 and / or a methoxyl percentage greater than about 22%; or (ii) a molar substitution of hydroxypropyl greater than about 0.21 moles of hydroxypropyl per mole of anhydroglucose and / or a percentage of hydroxypropyl greater than about 8.1%.

19. The process of claim 17 or 18, CHARACTERIZED by the fact that step (a) comprises mixing about 48% of the total amount of ketorolac, or one of its salts or derivatives; and step (b) comprises mixing about 52% of the total amount of ketorolac, or one of its salts or derivatives.

20. USE of the composition as defined in any one of claims 1 to 16, CHARACTERIZED by being for preparing a medicament for the treatment of pain.

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